LLT1 is expressed on the surface of activated immune cells, such as B, T, NK and dendritic cells, but is absent from resting, naïve cells. The receptor for LLT1 is CD161, also known as NKRP1A. CD161 is found on NK cells and effector/memory T cells. In T cells, the CD161 receptor functions as a co-stimulator of TCR signalling, whereas in NK cells CD161 is a cytotoxicity inhibitory receptor that restricts killing of cells expressing the CD161-ligand, LLT1.
In chronic autoimmune diseases such as inflammatory bowel diseases (ulcerative colitis and Crohn's disease), LLT1 expression is increased due to its presence on subsets of infiltrating inflammatory immune cells. CD161+T cells home to the intestine and are markedly up-regulated, in number, in inflamed tissue from patients with Crohn's disease. Certain lymphomas, such as follicular lymphomas, are also characterized by LLT1 expression.
Several anti-LLT1 monoclonal antibodies have been described in the literature and/or are commercial available. One of these, L9.7, was reported to bind specifically to LLT1 and to induce IFNγ secretion by NK cells without affecting the cytotoxic response (Mathew et al., 2004). Rosen et al. (2008) describes two murine anti-LLT1 monoclonal antibodies, 402624 and 402659 (the latter is now commercially available via R&D Systems, product No. MAB3480). Roth et al. (2007) describes the murine anti-LLT1 monoclonal antibody 4C7. None of these three antibodies block the interaction between LLT1 and CD161.
Biological therapeutics are now available for the treatment of certain autoimmune diseases and/or cancer. For example, patients with cancer may be treated with anti-CD20; patients with rheumatoid arthritis may be treated with anti-CD20, a TNF-R antagonist or anti-TNF-α; patients with psoriasis may be treated with anti-CD11a; patients with multiple sclerosis may be treated with INF-y; patients with ulcerative colitis may be treated with TNF-a and patients with Crohn's disease may be treated with Infliximab or Natalizumab. Unfortunately, patients that receive treatment with any one of these biologicals also experience a variety of dramatic side-effects and/or are non-responders and/or develop inhibitors. There is still a need for alternative biological medicaments which specifically target pathological tissue and/or which do not affect healthy tissue and/or which result in less severe side effects, and/or which result in fewer side effects, and/or which may be used long-term and/or which do not result in the formation of inhibitors. The current invention relates to these unmet needs amongst patients with cancer, and in those with autoimmune diseases and in those with chronic inflammatory diseases.